A group of phenotypically similar gigantism/overgrowth syndromes include one X-linked form, Simpson-Golabi-Behmel (SGBS) syndrome. Although a number of similar conditions map to various loci in 11p15.5, making the etiology of those diseases complex, we showed that SGBS results unequivocally from loss-of-function mutations in the glypican 3 (GPC3) gene. Nearly all of the very great genomic extent of the gene (more than 600 kb) has been sequenced and analyzed, and physiological studies of the gene have begun. Studies of the promoter have shown that it contains primary transcription factor sites that are methylated to shut it down in X-inactivated chromosomes; but in several types of cells transcription fails even in the absence of methylation, so that additional transcription factors must be involved in determining the tight tissue distribution of the gene. The tissue specificity overlaps the expression pattern of IGF2 very closely, so that GPC3 is likely involved in growth control in a pathway overlapping IGF2 function. In a mouse model, in collaboration with the Laboratories of Drs. G. Pilia and A. Efstradiatis, we have now disrupted gpc3 in mice and analyzed the resultant phenotype. The knockout mice show features of overgrowth. The interactions of gpc3 with genes in the igf2 growth regulatory pathway have been assessed in crosses of mice modified in various genes. The results show that gpc3 acts in a pathway independent of ifg2 action, but the two pathways very likely converge at a common point. In an independent approach, we are now attempting to find additional genes or pathways that can give rise to overgrowth, by investigating genes interrupted by translocations in sporadic cases of gigantism. A new candidate region for overgrowth control has been identified, and mapping and sequencing are now ongoing to find out if it marks another gene involved in the overall determination of the set point for organ and body size.